First Antisense Oligo Approved for Gene Knockdown in Liver

In a milestone for antisense oligonucleotide technology, Kynamro (aka mipomersen) yesterday received US regulatory approval for the treatment of homozygous familial hypercholesterolemia (hoFH).  It is the first regulatory approval for a systemically delivered oligonucleotide-based drug addressing a target in the liver, following two locally applied oligonucleotide drugs (aptamer Macugen and antisense oligo Vitravene) that have been approved for ocular diseases.  Considering that next month a TLR oligo-enhanced HepB vaccine by Dynavax could join the ranks of oligonucleotides licensed for medical use, oligo drug technology is rapidly shedding its image as an oddball technology and going mainstream.

Commercial Prospects

The hope, of course, is that Kynamro will also be the first commercially meaningful oligonucleotide considering lackluster sales histories by Macugen and Vitravene.  Favoring such success is the strong pricing power with drugs for orphan indications such as hoFH which is estimated to affect 3000 patients in the US and Europe each.  Small molecule drug Juxtapid by Aegerion for example received approval for the same indication last month and will price at $250.000 per annum.  With 1000 patients on the drug, this would mean sales of $250M already. And with the fudgible definition of symptomatic, instead of strictly genetically defined homoFH and the aggressive ‘friending’ of orphan drug salesforces with disease groups, I expect quite a bit of ‘label creep’ (Aegerion's CEO has indicated that he expects hoFH patients to somewhat respond to PCSK9 inhibitors which I can only explain if the patient population he considers homoFH includes quite a few non-hoFH when defined genetically).

With an expected price for Kynamro of $100k per annum, I optimistically project around $100M in annual sales assuming marketing partner Genzyme can get 1000 patients on drug in the US. With a ~35% profit share, a 50% profit margin and 50% attrition, ISIS Pharmaceuticals would pocket around $10M in annual profit share from this approval in a few years.

Update 30Jan13: It appears that according to a WSJ article (to which I cannot get access), Kynamro will be priced at $176k per year.  This, of course, would significantly improve ISIS profit share assuming same patient numbers treated (possibly 70% profit margin, slightly higher royalty rate in addition to higher sales --> $20-25M p.a.).

   

RNAi versus Antisense for gene knockdown in the liver

To maintain such sales numbers, however, the salesforce will have to fight hard to keep patients on the drug.  During the extension of the phase III study in homoFH, over half of patients  discontinued due to safety and tolerability issues, injection site reactions and liver safety (prompting a Black Box warning) being the main culprits. Having said that, the label for Juxtapid does not look any better, in fact a bit worse with all the intestinal side effects and drug-drug interactions, offset, however, by the increased potency in LDL-c lowering.

As some of the side effects are not target-specific (e.g. the injection site reactions and flu-like symptoms and also some of the liver enzyme elevations which are not fully accounted for by the liver fat elevations), the modest tolerability of and safety concerns with Kynamro (including vasculitis as well as liver and skin cancers especially when considering the preclinical data) raises the question whether systemically delivered phosphorothioate-based antisense technology has much of a future for gene knockdown in the liver also in light of increasing competition from RNAi delivery technologies.  You will not be surprised that I subscribe to the view that among Tekmira’s SNALP and the subcutaneous alternatives by Arrowhead (DPC) and Alnylam (GalNAc), RNAi will become the preferred technology for gene knockdown in the liver.

Whether RNAi or antisense, oligonucleotide therapeutics are here to stay.